Viscous or viscoelastic agents used in surgery may perform a number of different functions, including without limitation maintenance and support of soft tissue, tissue manipulation, lubrication, tissue protection, and adhesion prevention. It is recognized that the differing rheological properties of these agents will necessarily impact their ability to perform these functions, and, as a result, their suitability for certain surgical procedures. See, for example, U.S. Pat. No. 5,273,056.
Cataracts are opacities of the ocular lens which generally arise in the elderly. In order to improve eyesight, the cataractous lens is surgically removed and an artificial intraocular lens is inserted in its place. During these surgical procedures, viscoelastic materials are typically injected in the anterior chamber and capsular bag to prevent collapse of the anterior chamber and to protect tissue from damage resulting from physical manipulation.
A number of viscous or viscoelastic agents (hereinafter “agents”) are known for ophthalmic surgical use. For example, Viscoat® (Alcon Laboratories, Inc.) which contains sodium hyaluronate and chondroitin sulfate; Healon® and Healon® GV (Pharmacia Corp.), Amvisc® Regular and Amvisc® Plus (IOLAB), and Vitrax® (Allergan) all of which contain sodium hyaluronate; and Cellugel® (Alcon) which contains hydroxypropylmethylcellulose (HPMC) are all useful in cataract surgery. They are used by the skilled ophthalmic surgeon for several purposes: maintenance of the anterior chamber of the eye and protection of ophthalmic tissues during surgery, particularly corneal endothelial cells, and as an aid in manipulating ophthalmic tissues.
While all of the agents described above may be used during cataract surgery, each has certain recognized advantages and disadvantages. See, U.S. Pat. No. 5,273,056. Generally, however, all such agents having sufficient viscosity and pseudoplasticity to be useful in ophthalmic surgery will, if left in the eye at the close of surgery, result in a transient increase in intraocular pressure (“IOP”) known as an “IOP spike.” (See, Obstbaum, Postoperative pressure elevation. A rational approach to its prevention and management, J. Cataract Refractive Surgery 18:1 (1992).) The pressure increase has been attributed to the agent's interference with the normal outflow of aqueous humor through the trabecular meshwork and Schlemm's canal. (See, Berson et al., Obstruction of Aqueous Outflow by Sodium Hyaluronate in Enucleated Human Eyes, Am. J. Ophthalmology 95:668 (1983); Olivius et al., Intraocularpressure after cataract surgery with Healon®, Am. Intraocular Implant Soc. J. 11:480 (1985); Fry, Postoperative intraocular pressure rises: A comparison of Healon, Amvis, and Viscoat, J. Cataract Refractive Surgery 15:415 (1989).) IOP spikes, depending on their magnitude and duration, can cause significant and/or irreversible damage to susceptible ocular tissues, including, without limitation, the optic nerve.
Thus, the ease with which an agent can be removed from the surgical site, typically by aspiration, has traditionally been considered an important characteristic in the overall assessment of the agent's usefulness in cataract surgery. By removing the agent before the close of surgery, the surgeon hopes to minimize or avoid any significant IOP spike. Unfortunately, however, removal of agents which are relatively dispersive (as opposed to cohesive) or which adhere to the ocular tissue is often difficult and may cause additional trauma to the eye.
Exogenous dilution of the viscoelastic has been suggested to alleviate IOP spikes. See U.S. Pat. No. 4,328,803. Depending, however, on the particular viscoelastic and the surgical technique employed, IOP spike may still be a problem. More recently, it has been suggested that the administration of degradative agents to break down conventional viscous or viscoelastic agents in the eye can reduce or avoid the occurrence of IOP spikes. See, e.g., U.S. Pat. No. 5,792,103. Such an approach requires not only the administration of a second, enzymatic agent into the eye, the biocompatibility of which must be assured; but also means for adequately mixing the two agents in a special apparatus.
Viscoelastics have also been promoted as drug delivery devices for pharmaceutical agents which are administered when the viscoelastics are applied during surgery. For example, U.S. Pat. No. 5,811,453 (Yanni et al.) discloses viscoelastics containing anti-inflammatory compounds and methods of using these enhanced viscoelastics in cataract surgery. While this approach may ameliorate ocular inflammation resulting from surgical trauma, such an approach still possesses the significant limitation of presenting IOP spike problems, as described above. Consequently, these enhanced viscoelastics still need to be aspirated out at the close of surgery.
There is, therefore, a need for an improved means for reducing or avoiding IOP spikes associated with the use of conventional viscous or viscoelastic agents in ophthalmic surgery, especially cataract surgery. More specifically, we conceived the need for an improved viscous or viscoelastic agent having a variable or transitional viscosity such that it will, without the addition of degradation agents, become substantially less viscous after its purpose has been served in surgery, such agents being hereinafter referred to as transitional viscoelastics. Such transitional viscoelastics may then be left by the surgeon to be eliminated gradually from the surgical site by the body's natural processes without creating a dangerous IOP spike.
Transitional viscosities are known to occur in certain agents systems. In the ophthalmic field, systems are known in which a liquid forms a gel after application to the eye. For example, such gelations may be triggered by a change in pH. See, Gurney et al., “The Development and Use of In Situ Formed Gels, Triggered by pH” Biopharm. Ocul. Drug Delivery, (1993) pp. 81–90. Temperature sensitive gelation systems have also been observed for certain ethyl (hydroxyethyl) cellulose ethers (EHECs) when mixed with particular ionic surfactants at appropriate concentrations. See, Carlsson et al., “Thermal Gelation of Nonionic Cellulose Ethers and Ionic Surfactants in Water” Colloids Surf., volume 47, pages 147–65 (1990) and for systems of pure methylethyl cellulose, U.S. Pat. No. 5,618,800 (Kabra et al.)) Likewise, gellan gum (Gelrite®) is known to form a gel on contact with specific cations. Greaves et al., “Scintigraphic Assessment of an Ophthalmic Gelling Vehicle in Man and Rabbit,” Curr. Eye Res., volume 9, page 415 (1990). Gellan systems have been suggested for use as a vehicle for ophthalmic medications (Rozier et al., “Gelrite: A Novel, Ion-Activated, In Situ Gelling Polymer for Ophthalmic Vehicles. Effect on Bioavailability of Timolol,” Int. J. Pharm., volume 57, page 163 (1989)), and one gellan system is currently being marketed with timolol, a beta blocker, as a glaucoma medication. Carrageenans also have been suggested for use as a delivery vehicle for ophthalmic drugs. See, e.g. U.S. Pat. Nos. 5,403,841 and 5,965,152, the contents of both of which are by this reference incorporated herein. U.S. Pat. No. 5,403,841 and EP0 424043 disclose ophthalmic carrageenan compositions which transition from liquid to gel when topically applied to the eye. Finally, it is known that carrageenans can be tailored to adjust their viscosity transitions to different temperature ranges. (See, Verschueren et al. “Evaluation of various carrageenans as ophthalmic viscolysers” STP Pharma Sci., volume 6, pages 203–210 (1996), and Picullel et al., “Gelling Carragreenans,” Food Polysaccharides and their Applications, Ed: Stephen, A. M., Marcel Dekker: New York, volume 67, pages 204–44 (1995).) Kappa-carrageenans, for example, are polysaccharides which display a temperature dependent conformation wherein at high temperature the molecules exist as random coils. As the temperature is lowered, the chains associate into double helices, and, depending on the amount of potassium (K+) in the solution, the double helices then self-associate into a three dimensional network. The gel formed by potassium cross-linked kappa-carrageenan is, unfortunately, very brittle, resembling the gels formed by calcium cross-linked alginate and pectin. All of these gels also exhibit syneresis, a process wherein the formation of the gel is so favored that the solvent (physiologic aqueous media here) is forced out from the gel network.
The use of a transitional viscosity viscoelastic agent as an effective surgical tool, however, especially in ophthalmic surgery, has neither been disclosed or suggested in the art. To be effective for use as an ophthalmic surgical tool, the agent, in addition to having the desired initial and transitional viscosities over the prescribed temperature range, would need to meet the following requirements: physiologically acceptable osmolarity and pH; relatively short viscosity transition time; clear (without turbidity); biocompatible; and sterilizable. The transitional viscoelastics of the present invention are believed to satisfy these requirements